HERC2P2调控DNA损伤修复及胶质瘤TMZ化疗增敏：ceRNA作用的新机制

项目名称： HERC2P2调控DNA损伤修复及胶质瘤TMZ化疗增敏：ceRNA作用的新机制

项目编号： No.81502619

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 王琦雪

作者单位： 天津医科大学

项目金额： 18万元

中文摘要： RNA调控网络的异常在肿瘤的发展中起到重要作用，由miRNA介导的，lncRNA和mRNA之间的竞争性内源RNA(ceRNA)的调控作用，则是近期的研究热点。课题组前期对国人胶质瘤ceRNA的研究发现，长链非编码RNA(lncRNA)HERC2P2处于核心地位，并与病人生存率正相关。据此，我们提出科学假说，HERC2P2调控DNA损伤修复是胶质瘤TMZ化疗增敏的新机制。我们拟用RNA免疫共沉淀、荧光素酶技术等实验检测ceRNA桥梁基因miR-590-3p介导HERC2P2与L3MBTL1的相互调控；在胶质瘤细胞系中恢复HERC2P2的表达，验证其对DNA损伤修复和TMZ敏感性的影响；在裸鼠模型中研究过表达HERC2P2或敲低miR-590-3p，对TMZ的敏感性和生存率的变化。我们将鉴定胶质瘤中全新的抑癌基因HERC2P2，揭示胶质瘤对TMZ原发性耐药的新机制。

中文关键词： 胶质瘤；竞争性内源RNA；长链非编码RNA；HERC2P2；L3MBTL1

英文摘要： The abnormal of RNA interaction plays an important role in the progress of tumor, while competitive endogenous RNA (ceRNA) is the hotspot of research. In recent study, we find out that long non-coding RNA (lncRNA) HERC2P2 is positively correlated with the survival rate of glioma patients, which means that HERC2P2 is a tumor supressor. Thus, we hypothesize that HERC2P2 regulates DNA double strand breaking repair and enhances chemosensitivity of TMZ on GBM in a ceRNA mechanism. In particular, HERC2P2 may act as a ceRNA, effectively becoming a sink for miR-590-3p, thereby modulating the derepression of L3MBTL1 and imposing an additional level of post-transcriptional regulation. Based on the hypothesis, we intend to investigate ceRNA regulation of HERC2P2 /L3MBTL1 by IP, CHIP and luciferase report assays. Next we will overexpress HERC2P2 in GBM cells and examine the sensitivity of GBM cells to TMZ. What's more, we'll investigate the inhibition efforts of overexpression HERC2P2 or knock down miR-590-3p on GBM growth in mice. In conclusion, our group will identify lncRNA HERC2P2 as a glioma inhibitor for the first time, revealing new resistance mechanism to TMZ, and providing more potential approaches to GBM treatment.

英文关键词： Glioma;ceRNA;long non-coding RNA;HERC2P2;L3MBTL1